B2-5 Mutations

Question 1

Mutations

Answer 1

Rare
Permanent change in DNA
Alteration to an organism’s characteristics

Question 2

Germline Mutation

Answer 2

Occurs in germline cells (consisting of germ cells and gametes). May be transmitted to offspring and to successive generations

If mutation has an adverse effect on the phenotype of an organism, the mutant condition is referred to as a genetic disorder, or hereditary disease

Question 3

Somatic Mutation

Answer 3

Occurs in somatic cells

Not inherited by the progeny and hence not passed on to the next generation

Question 4

Gene / Point Mutations

Answer 4

Involve chemical changes that affect DNA sequence of just 1 gene
Involve changes at specific sites in a gene, resulting in a change in one or few bases in the DNA sequence

Question 5

Nucleotide Substitution (4 types)

Answer 5

The replacement of 1 nucleotide pair with another, resulting in one of the following

Missense mutation – Nucleotide substitution in a DNA sequence results in translation of different aa

Nonsense mutation – Nucleotide substitution in a DNA sequence results in codon for aa being changed into a stop codon, leading to the premature termination of translation

Silent mutation – Nucleotide substitution in a DNA sequence changes mRNA codon, however same aa is inserted into the protein because of the degeneracy of the genetic code

Neutral mutation - Nucleotide substitution in a DNA sequence changes mRNA codon and aa translated. However, the resulting aa substitution produces no detectable change in function of protein translated

Question 6

Nucleotide Insertions or Deletions

Answer 6

Addition or deletion of 1 or more nucleotide pairs

Addition or deletion of deoxynucleotides in multiples of 3
Missense mutation – mRNA codon added or deleted, resulting polypeptide has aa added or deleted respectively
OR
Nonsense mutation – Stop codon added, leading to premature termination of translation

Addition or deletion of deoxyribonucleotides not in multiples of 3
Frameshift mutation – mRNA codons subsequent to insertion or deletion are changed, resulting in
2 types
Extensive missense mutation – Subsequent aa sequence of the polypeptide is changed
OR
Nonsense mutation – Codon for aa is changed to a stop codon, resulting in a truncated protein

Question 7

Missense Mutation

Answer 7

Nucleotide substitution in a DNA sequence changes the mRNA codon, resulting in translation of a different aa

AA sequence of polypeptide is changed, resulting in a change in the specific 3D conformation of the protein, hence function of protein is altered E.g. Sickle cell anaemia

Question 8

Nonsense Mutation

Answer 8

Nucleotide substitution in a DNA sequence changes a codon for an aa into a stop codon, resulting in premature termination of translation
Resulting polypeptide will be shorter (truncated) than the normal polypeptide encoded

AA sequence of polypeptide is shortened, resulting in a change in the specific 3D conformation of the protein. Hence, function of protein is altered.
Nearly all nonsense mutations result in non-functional proteins

Question 9

Silent Mutation

Answer 9

Nucleotide substitution in a DNA sequence changes the mRNA codon. However, the same aa is inserted into the polypeptide because of the degeneracy of the genetic code

AA sequence of the polypeptide is unchanged, resulting in no change in the specific 3D conformation of the protein. Hence, function of the protein is unaltered.

Question 10

Neutral Mutation

Answer 10

Nucleotide substitution in a DNA sequence changes the mRNA codon. However, the resulting aa produces no detectable change in the function of the protein translated.

This could arise from
Substitution of the original aa with an aa of similar physical and chemical properties
OR
Substitution of an aa residue that is non-essential to that protein’s structure and function

AA sequence of polypeptide is changed, but there is no change in the overall 3D conformation of the protein and hence the function of the protein is not altered.

Question 11

Effects of Nucleotide Insertions or Deletions

Answer 11

Additions or losses, respectively, nucleotide pairs in a gene, often has deleterious effects
As the resulting mRNA is read as a series of non-overlapping codons, an insertion or deletion of nucleotides not in multiples of 3s will result in a frameshift mutation
All nucleotides downstream of insertion/deletion site will be improperly grouped into codons, resulting in extensive missense

The frameshift may also cause a new, premature stop codon (nonsense mutation) to be generated in the reading frame, or result in a read-through of the normal stop codon, resulting in polypeptides of altered lengths. In any case, a frameshift usually results in a non-functional protein.

Question 12

Gene Mutation resulting in Phenotypic Change – Sickle-Cell Anaemia

Answer 12

Mutation in the B-globin gene, which encodes 1 of the polypeptide subunits that make up haemoglobin

Genetic and molecular basis:
Substitution of a thymine for an adenine at 1 position in the Hb gene, which results in a missense mutation
Sixth aa residue in polypeptide is changed from a glutamate (hydrophilic) to a valine (hydrophobic)

Specific 3D conformation and function of the Hb protein is altered
Substitution creates a hydrophobic spot on the outside of the Hb protein that sticks to the hydrophobic region of an adjacent Hb protein’s beta chain.

The mutant Hb subunits tend to stick to one another when the oxygen concentration is low, particularly when the rbcs are in capillaries and veins
The aggregated proteins form fibre-like structures within rbcs
At high oxygen concentration, haemoglobin resumes globular haemoglobin structure

Physiological effects:
Fibre-like structures cause the rbcs to lose their normal morphology and become sickle-shaped. Sickled cells are less able to move through capillaries and can block blood flow, resulting in severe pain and cell death of the surrounding tissues due to shortage in oxygen

Sickled rbcs are also fragile and easily destroyed, further decreasing the oxygen carrying capacity of blood

Question 13

Causes of Mutations -
Spontaneous Mutations

• Mutations that occur naturally I.e. without the use of chemical or physical mutagenic agents
• May be the result of errors that occur during DNA replication, recombination or repair (can lead to both gene and chromosomal mutations)

Answer 13

A. DNA replication and repair

Mistakes: Although DNA replicates with fairly high fidelity, mistakes do happen. DNA polymerase sometimes inserts the wrong nucleotide / too many / too few nucleotides into DNA sequence.
DNA polymerase makes mistakes at a rate of about 1 in every 100 000 nucleotides. With our 6 billion bp in each diploid human cell, that would be about 120 000 mistakes every time a cell divides.

Attempts at Correction: Some of the mistakes are corrected immediately during replication through a process known as proofreading, and some are corrected after replication in a process called mismatch repair.
During proofreading, DNA polymerase enzymes recognise mistakes and replace the incorrectly inserted nucleotides so that replication can continue.

After replication, mismatch repair reduces the final error rate even further. Incorrectly paired nucleotides cause deformities in the secondary structure of the final DNA molecule. During mismatch repair, enzymes recognise and fix these deformities by removing the incorrectly paired nucleotide and replacing it with the correct nucleotide.

Some replication errors fail to be recognised by the repair enzymes and these altered nucleotides sequences can then be passed down from one cellular generation to the next. And if they occur in cells that give rise to gametes, they can even be transmitted to subsequent generations of the organism.

B. DNA Slippage

Daughter or parental DNA strand slips during DNA replication followed by folding back of the strand.

Hence, there is mispairing between the daughter DNA strand and the parental template strand.

This causes parts of the DNA which are folded back to be copied more than once. If this duplicated DNA segment corresponds to a gene, it will result in gene duplication.

Question 14

Causes of Mutations - Induced Mutations

Answer 14

Induced Mutations

Result of deliberate application of mutagens (chemical or physical agents) that result in increased mutation rates

Commonly performed in the study of genetics in order to allow geneticists to study the effects of mutations in specific genes

Question 15

Chromosomal Mutation / Aberration

Answer 15

Defined as change in structure of a chromosome or number of chromosomes

Question 16

Change in Chromosome Structure (4 types)

Answer 16

Deletion
Duplication
Inversion
Translocation

Question 17

Deletion

Answer 17

When a chromosome breaks in one or more places, the missing piece is referred to as a deletion. The deletion can occur near one end or from the interior of the chromosome. These are called terminal or intercalary deletions respectively.

Effect of a deletion is usually profound, in which the genotype is altered due to absence of certain gene loci. If a deletion affects the same gene loci on both homologous chromosomes, the effect is usually lethal. If only one of a homologous pair of chromosomes is affected, the effect on the phenotype is that alleles on the non-deficient homologue will be expressed, even if recessive.

Question 18

Duplication

Answer 18

When any part of the genetic material is present more than once in the genome, it is called duplication. Duplications can arise as a result of unequal crossing over between synapsed chromosomes during meiosis or through a replication error prior to meiosis. In the former case, both duplication and deletion are produced.

Effects of duplications include gene redundancy and phenotypic variations. In addition, duplications have also been deemed as an important source of genetic variation during evolution.

Question 19

Inversion

Answer 19

A segment of chromosome is turned around 180 degrees within a chromosome. An inversion does not involve a loss of genetic information, but simply rearranges the linear sequence. It requires 2 breaks along the length of the chromosome and subsequent reinsertion of the inverted segment. By forming a chromosomal loop prior to breakage, the newly created “sticky” ends are brought close together and rejoined.

Organisms heterozygous for inversions may produce aberrant gametes that have a major impact on their offspring. In addition, inversions may also result in position effects which lead to altered gene expression due to new positioning of a gene within the genome and thus play an important role in the evolutionary process.

Question 20

Translocation

Answer 20

Movement of a chromosomal segment to a new location in the genome. Reciprocal translocation involves the exchange of segments between 2 non-homologous chromosomes.

Genetic consequences of reciprocal translocation are rather similar to those of inversions. For instance, genetic information is not lost or gained, but there is only a rearrangement of genetic material. Hence, the presence of a translocation does not directly alter the viability of individuals bearing it. Like an inversion, a translocation may also produce a position effect as it may realign certain genes in relation to other genes.

Question 21

Change in Chromosome Number

Answer 21

Variation in chromosome number ranges from the addition or loss of one or more chromosomes (aneuploidy – 2n+1) to the addition of one or more haploid sets of chromosomes (polyploidy – 3n,4n)

Question 22

Aneuploidy

Answer 22

General condition in which an organism loses or gains one or more chromosomes, but not a complete set.

Originate as a random error during the production of gametes.
Non-disjunction is the failure of chromosomes or chromatids to disjoin and move to opposite poles during division. When this occurs in meiosis, the normal distribution of chromosomes into gametes is disrupted.

Loss of a single chromosome from an otherwise diploid genome: Monosomy
Gain of one chromosome: Trisomy

Monosomy
In humans only occurs for the X chromosome
Monosomy for any of the autosomes is usually not tolerated in humans or other animals

Trisomy
Down syndrome, which is the only human autosomal trisomy in which a significant number of individuals survive longer than a year past birth
Affected individuals have an extra chromosome 21. These individuals are characteristically short, have skin folds over the corner of their eyes, stocky bodies and thick necks. They are also prone to heart abnormalities and have short life expectancy, and have low intelligence level.

Question 23

Polyploidy

Answer 23

Euploidy: Multiples of the haploid chromosome set are found

In particular, polyploidy: More than 2 multiples of the haploid chromosome set are found
Triploid – 3n chromosomes, Tetraploid – 4n chromosomes, so on
Relatively infrequent in many animal species, but is well known in lizards, amphibians, and fish + Much more common in plants

Can originate in 2 ways:
Addition of 1 or more extra sets of chromosomes identical to the normal haploid component of the same species resulting in autoploidy

Combination of chromosome sets from different species may occur as a consequence of interspecific matings resulting in allopolyploidy

Distinction between auto- and allopolyploidy is based on genetic origin of extra chromosome sets

Question 24

Autoploidy

Answer 24

May occur when all chromosomes fail to segregate during meiotic divisions, producing a diploid gamete
Fertilisation by a haploid gamete results in a triploid zygote
Triploids can also be produced under experimental conditions by crossing with tetraploids - gamete from diploid has n chromosomes, from tetraploid has 2n chromosomes - triploid produced upon fertilisation

Autotetraploids are theoretically more likely to be found in nature than autotriploids due to their even number of chromosomes
Unlike triploids which often produce genetically unbalanced gametes with odd number of chromosomes, tetraploids are more likely to produce balanced gametes when involved in sexual reproduction
Tetraploid species e.g. coffee, peanuts are also of economic value due to larger sizes or more vigorous growth than their diploid or triploid counterparts

Question 25

Alloploidy

Answer 25

Results from hybridisation of 2 closely related species
Haploid ovum from a species with chromosome sets AA is fertilised by a haploid sperm from a species with sets BB, resulting hybrid is AB
Hybrid plant may be sterile because of its inability to produce viable gametes - occurs when some, or all, of the a and b chromosomes are not homologous and thus are unable to synapse in meiosis - unbalanced genetic conditions
However, if new AB genetic combination undergoes a natural or induced chromosomal doubling, 2 copies of all a chromosomes and 2 copies of all b chromosomes are now present, and they will pair during meiosis
As a result, fertile AABB tetraploid produced

When both original species are known, equivalent term amphidiploid is preferred for describing the allotetraploid